Among the most devastating diseases are those of the central nervous system (CNS). Profoundly disabling and chronic, they wreak emotional, physical, and economic havoc upon individuals, their families, and society. In the 2000 report by the Family Caregiver Alliance (www.caregiver.org), 1.1 million new cases of the 10 most common brain diseases were diagnosed in the U.S. alone. More than 16 million patients receive ongoing care for these diseases, many of whom might still benefit from more effective therapeutic modalities. Among the most promising interventions is "restorative neurosurgery." Traditionally, neurosurgical intervention has involved removal of pathological tissues. In restorative neurosurgery, however, therapeutic agents or tissues are introduced within distinct regions of the CNS using a minimally-invasive stereotactic surgical procedure. Restorative therapeutics include trophic factors, gene therapy vectors, chemo-therapeutics, therapeutic cells (neural transplantation), or other neuroactive compounds. Optimizing the benefits of restorative therapeutics will depend on a neurosurgeon's ability to deliver these medicines with exquisite accuracy and minimal damage to functionally normal tissue. Stereotactic surgery allows procedures to be performed on structures deep within the brain with reduced, but not negligible, damage to tissue above and surrounding the target structure. Stereotactic injection of therapeutic cells, for example, holds promise as a method for reconstituting cell populations, supplementing levels of locally produced brain chemicals, and re-establishing neural circuitry. One focus of the original SBIR grant application was to address the shortcomings in the methodology and instrumentation used for neural transplantation. Despite some successes, functional recovery following brain cell injections has been modest and highly variable to date. Marginal patient recovery has been directly associated with the implanted cells'poor survival rate;increasing the success of neural cell engraftment would substantially advance the utility of this potentially powerful therapeutic approach. Animal studies have demonstrated that transplanted cell survival rates increase when the injection instrument used to deliver cells into the brain is smaller and the injection volume reduced. "Microvolumes" of cells (0.25 2 5L) delivered through a pulled glass micropipette with a final diameter of approximately 70 microns have a survival rate 250% or greater higher than larger cell volumes (5-20 5L) injected through a 0.5 mm-diameter cannula. Commonly used injectors for human surgery are 0.5-1 mm in diameter, and graft volume is typically 10-20 5L. SBIR funding has enabled the development of an Intracerebral Microinjection Instrument (IMI) that permits precise micro-volumes of therapeutic agent to be stereotacticly placed in a three-dimensional array within the human brain using a single penetration of overlying tissue by a "guide" cannula. The IMI delivery cannula is extremely small, ranging from 20 to 200 micrometers in diameter. It is capable of electrophysiological recording before, during, and after delivery of the therapeutic, permitting exquisite targeting precision. In addition to neural transplantation, the IMI is particularly well-suited for direct delivery of a variety of agents, including those used for chemotherapy. Indeed, neurosurgical treatment for glioblastoma multiforme, an aggressively malignant and deadly carcinoma, may be a primary indication for the IMI. This proposal is for improvements to this instrument, preparing it for use in neurosurgical approaches for human diseases of the CNS, and to obtain funding for the FDA market clearance of the technology. PUBLIC HEALTH RELEVANCE: An emerging area of neurosurgical treatment of brain disease involves inserting chemotherapeutics, cells, antioxidants, or other therapeutic agents directly into brain in order to bypass the blood/brain barrier, and in order to achieve concentration at a precise anatomical site in brain. The Intracerebral Microinjection Instrument proposed herein improves the ability to make such injections with minimal damage to the brain, and with minimal activation of the brains rejection mechanisms for foreign material.